α,ω-Dicarboxylic acid-terminated dialkane ethers have activity in lowering several plasma lipids, including Lp(a), triglycerides, VLDL-cholesterol, and LDL-cholesterol, both in animals and in humans. See U.S. Pub. No. 2010/0256209. The compounds also are known to increase insulin sensitivity. See U.S. Pub. No. 2010/0256209. In particular, 6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid) (also known as 6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid), whose USAN name is gemcabene, and its calcium salt (gemcabene calcium) have been intensively studied in multiple clinical trials as a lipid lowering agent for the treatment of patients with low high-density lipoprotein (HDL) and high low density lipoprotein (LDL). See Bays, H. E., et al., Amer. J. Cardiology, 2003, 92, 538-543. Gemcabene has been clinically tested as an anti-hypertensive and anti-diabetic agent in addition to the lipid lowering activity.
A synthetic method for the preparation of 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) and other α,ω-dicarboxylic acid-terminated dialkane ethers is described by Bisgaier, C. L. et al. in U.S. Pat. No. 5,648,387, which is incorporated herein by reference in its entirety. In addition, preparation and characterization of alcohol and water solvates of 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium (gemcabene calcium), for the treatment of dyslipidemia, vascular disease, and diabetes are disclosed in U.S. Pat. No. 6,861,555, which is incorporated herein by reference in its entirety. Zhang, Y et al. also report a small scale synthesis of C-14- and tritiated-gemcabene congeners in J Label Compd Radiopharm 2007, 50, 602-604.
The previously disclosed syntheses raise a number of safety and environmental concerns when replicated on a scale larger than 1 kg. Thus, a need remains for safe and environmentally friendly processes for preparing α,ω-dicarboxylic acid-terminated dialkane ethers on a large scale.